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Shaquem Griffin was born to Terry and Tangie Griffin[10] on July 20, 1995, less than two minutes after Shaquill.[11][12] Shaquem was born with amniotic band syndrome affecting his left hand, causing his fingers on his left hand not to fully develop.[10][13][14] At age 4, his mother found him in the kitchen, attempting to use a butcher's knife to amputate his own hand because of the pain. His parents scheduled an amputation the next day.[10][12] Still, Griffin was able to continue playing sports without his left hand, competing in track, baseball, and football alongside his brother.[10]

In his second season, playing as a redshirt freshman, Shaquem Griffin had a brief stint as a second string player on the depth chart before being demoted to third string and then scout team. Griffin attributes his rise in his redshirt junior and redshirt senior seasons to Scott Frost's hiring as head coach for the 2016 and 2017 seasons. Writing for The Players' Tribune, Griffin said that, following his winless third season under O'Leary, "Coach Frost came in and brought me back into the light...He gave me the opportunity I had been waiting for ever since I first arrived at UCF. And I took advantage of it."[18]

Griffin was named the 2018 Peach Bowl Defensive MVP and was the 2016 American Athletic Conference Defensive Player of the Year. In Griffin's senior season, UCF went undefeated and subsequently claimed a controversial national championship.[a] Griffin told Ralph Warner and NFL Network in November 2017 that he planned to continue his football career in the NFL.

Shaquem stayed at UCF one season longer than Shaquill, as Shaquem redshirted his freshman year while Shaquill saw playing time.[22][23][24] Shaquill graduated and was drafted by the Seattle Seahawks in the third round (90th overall pick) of the 2017 NFL Draft,[25] while Shaquem stayed on for his redshirt senior year at UCF.

Despite not initially receiving an invitation,[28][29]
Griffin participated in the NFL Scouting Combine in March 2018. He made headlines for performing 20 reps in the bench press while wearing a prosthesis[30] and for running the 40-yard dash in 4.38 seconds, the fastest time for a linebacker since the NFL has released official statistics.[31]

Despite the fact that he was not projected as a first round pick, Griffin received an invitation to the 2018 NFL Draft, which he accepted on March 29, 2018.[34][35] Griffin received extensive press and social media coverage leading up to and during the draft, as he would have been the first one-handed player drafted into the NFL if chosen.[5][6][7][8] On April 28, 2018, he was selected by the Seattle Seahawks in the fifth round (141st overall), reuniting him with his brother Shaquill.[9][36] On May 17, 2018, Griffin signed a four-year deal worth $2.8 million with $300,000 guaranteed.[37]

On August 9, 2018 Griffin made his preseason debut against the Indianapolis Colts in CenturyLink Field, leading his team in tackles with six solo tackles and three assisted tackles. On August 30, 2018, he again led the team in tackles with four solo and three assisted tackles in the final week of the preseason against the Oakland Raiders. Griffin led the Seahawks in total tackles for the entire 2018 NFL preseason with fifteen, tied with fellow linebacker Austin Calitro.

On September 9, 2018, Griffin was named as a starter in the first game of his NFL career due to veteran linebacker K.J. Wright being unable to play. He made three solo tackles in the 27-24 loss to the Denver Broncos at Mile High Stadium.